Applications of RNA interference: current state and prospects for siRNA-based strategies in vivo

Aigner, Achim

doi:10.1007/s00253-007-0984-y

Cited by 108 publications

(56 citation statements)

References 133 publications

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“…Lastly, RNAi is widely used in genetic analysis to eliminate specific gene function and many practical applications of this tool have been suggested (Aigner 2007). The finding that chronic ectopic cell death alters the pattern of RNAi is critical for an understanding of the application of the technique in basic and applied studies.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of RNA Interference and Modulation of Transposable Element Expression by Cell Death in Drosophila

2011

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RNA interference (RNAi) regulates gene expression by sequence-specific destruction of RNA. It acts as a defense mechanism against viruses and represses the expression of transposable elements (TEs) and some endogenous genes. We report that mutations and transgene constructs that condition cell death suppress RNA interference in adjacent cells in Drosophila melanogaster. The reversal of RNAi is effective for both the white (w) eye color gene and green fluorescent protein (GFP), indicating the generality of the inhibition. Antiapoptotic transgenes that reverse cell death will also reverse the inhibition of RNAi. Using GFP and a low level of cell death produced by a heat shock-head involution defective (hs-hid) transgene, the inhibition appears to occur by blocking the conversion of double-stranded RNA (dsRNA) to short interfering RNA (siRNA). We also demonstrate that the mus308 gene and endogenous transposable elements, which are both regularly silenced by RNAi, are increased in expression and accompanied by a reduced level of siRNA, when cell death occurs. The finding that chronic ectopic cell death affects RNAi is critical for an understanding of the application of the technique in basic and applied studies. These results also suggest that developmental perturbations, disease states, or environmental insults that cause ectopic cell death would alter transposon and gene expression patterns in the organism by the inhibition of small RNA silencing processes.

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Section: Discussionmentioning

confidence: 99%

Inhibition of RNA Interference and Modulation of Transposable Element Expression by Cell Death in Drosophila

2011

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“…6 Target molecules usually represent genes that have been shown previously to be relevant or rate limiting for tumor growth, including growth factors and receptors as well as antiapoptotic or downstream signal transduction proteins in cancer cells. 7 Often these targeted molecules are not unique for cancer cells thereby limiting the therapeutic window or these molecules appear to be redundant leading to resistance. Therefore, targeting of molecules that are unique in cancer cells may lead to more specific therapeutic interventions.…”

Section: Introductionmentioning

confidence: 99%

Allele-specific cancer cell killing in vitro and in vivo targeting a single-nucleotide polymorphism in POLR2A

et al. 2009

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Cancer is one of the diseases for which RNA interference is a potential therapeutic approach. Genes involved in the promotion or maintenance of tumor growth are obvious targets for RNAi. RNAi is also considered an attractive additional approach to conventional chemotherapy for cancer treatment. Moreover, siRNAs have shown a high specificity for their molecular target mRNAs as they can selectively inhibit cancer-promoting genes that differ by a point mutation. Loss of heterozygosity (LOH) reduces genes to hemizygosity in cancer cells and presents an absolute difference between normal and cancer cells. The regions of LOH are usually much larger than the tumor suppressor gene, which is lost, and has been shown to contain genes that are essential for cell survival. Single-nucleotide polymorphisms (SNPs) are the most common type of genetic variation in man. SNPs in essential genes that are frequently affected by LOH can be used as a target for a therapy against cancer cells with LOH. We have designed siRNAs against the gene of the large subunit of RNA polymerase II (POLR2A), a gene located in close proximity to the tumor suppressor gene p53, which frequently shows LOH in cancer cells. It is shown in vitro that siRNA can selectively inhibit POLR2A expression dependent on its genotype. Furthermore, cancer cell proliferation and tumor growth inhibition in nude mice was genotype dependent. We conclude that siRNA can be used for genotype-specific inhibition of tumor growth targeting an SNP in POLR2A in vivo.

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“…RNA interference (RNAi) can be used as novel therapeutic modality through specific silencing of therapeutically relevant genes in vivo (1)(2)(3). In particular, chemically synthesized, small interfering RNAs (siRNA) are currently used as a new class of therapeutic molecules, allowing the controlled down-regulation of pathologically relevant gene expression as for oncogenes in cancer (4).…”

Section: Introductionmentioning

confidence: 99%

Atu027, a Liposomal Small Interfering RNA Formulation Targeting Protein Kinase N3, Inhibits Cancer Progression

et al. 2008

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We have previously described a small interfering RNA (siRNA) delivery system (AtuPLEX) for RNA interference (RNAi) in the vasculature of mice. Here we report preclinical data for Atu027, a siRNA-lipoplex directed against protein kinase N3 (PKN3), currently under development for the treatment of advanced solid cancer. In vitro studies revealed that Atu027-mediated inhibition of PKN3 function in primary endothelial cells impaired tube formation on extracellular matrix and cell migration, but is not essential for proliferation. Systemic administration of Atu027 by repeated bolus injections or infusions in mice, rats, and nonhuman primates results in specific, RNAi-mediated silencing of PKN3 expression. We show the efficacy of Atu027 in orthotopic mouse models for prostate and pancreatic cancers with significant inhibition of tumor growth and lymph node metastasis formation. The tumor vasculature of Atu027-treated animals showed a specific reduction in lymph vessel density but no significant changes in microvascular density. [Cancer Res 2008;68(23):9788-98]

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Applications of RNA interference: current state and prospects for siRNA-based strategies in vivo

Cited by 108 publications

References 133 publications

Inhibition of RNA Interference and Modulation of Transposable Element Expression by Cell Death in Drosophila

Inhibition of RNA Interference and Modulation of Transposable Element Expression by Cell Death in Drosophila

Allele-specific cancer cell killing in vitro and in vivo targeting a single-nucleotide polymorphism in POLR2A

Atu027, a Liposomal Small Interfering RNA Formulation Targeting Protein Kinase N3, Inhibits Cancer Progression

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